Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma

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1 ORIGINAL ARTICLE Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma Hong Kwan Kim, MD,* Yong Soo Choi, MD,* Jhingook Kim, MD, PhD,* Young Mog Shim, MD, PhD,* Kyung Soo Lee, MD, PhD, and Kwhanmien Kim, MD, PhD* Introduction: The objective of this study was to evaluate the clinical characteristics and long-term outcome of multiple pure ground-glass opacity (GGO) lesions detected in patients undergoing pulmonary resection for bronchioloalveolar carcinoma (BAC). Methods: Between January 2000 and December 2007, 73 patients underwent pulmonary resection for BAC. Of those, 23 patients had multiple pure GGOs on their preoperative computed tomography (CT) scans. Eighty-nine GGO lesions were detected with a median number of 3 (range, 2 11) per patient. Resection included wedge resection in 12 patients, lobectomy in 7, lobectomy with wedge resection in 3, and bilobectomy in 1. Five patients had all GGOs lesions resected (group I), whereas 18 had some of the GGO lesions resected and the remaining lesions followed by serial CT scans (group II). Median follow-up was 40.3 months. Results: No late death occurred during the follow-up period. In group I, four patients had no recurrences and one patient developed a new lesion that was resected and found to be adenocarcinoma. In group II, GGO lesions either did not change in size (n 15) or disappeared (n 3) in all patients. No GGO lesions increased in size or developed a solid component during the follow-up period. Conclusions: When multiple pure GGO lesions in patients with BAC remained without surgical resection, there was no change in their size or features during follow-up. When it is not feasible to resect all GGO lesions in patients with multifocal BAC, close follow-up using CT scans represents an alternative to surgical resection. Keywords: Ground-glass opacity, Bronchioloalveolar carcinoma, Follow-up, Surgical resection. (J Thorac Oncol. 2010;5: ) *Department of Thoracic and Cardiovascular Surgery, and Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Kwhanmien Kim, MD, Department of Thoracic Surgery, Samsung Medical Center, 50 Ilwon-dong, Gangnam-gu, Seoul , Korea. kmkim0070@yahoo.co.kr Copyright 2010 by the International Association for the Study of Lung Cancer ISSN: /10/ With recent advances in diagnostic imaging modalities, pure ground-glass opacity (GGO) lesions have been increasingly detected on high-resolution computed tomography (HRCT) scans. 1 4 The correlation between the radiologic findings of GGO lesions and their pathologic diagnosis has been extensively studied As GGO is a nonspecific finding, it can be caused by various diseases such as inflammation, fibrosis, or neoplasm. 5 In particular, with respect to pure GGO, the possibility of nonmucinous bronchioloalveolar carcinoma (BAC) cannot be excluded. Indeed, BAC usually appears as multiple pure GGO lesions. Previous genetic research on BAC using a novel strategy for clonality determination indicates that these tumors are mostly multifocal, independent cancers. 13 Accordingly, in patients with multiple pure GGO lesions on HRCT scans, when one of the lesions is pathologically confirmed as BAC, the remaining lesions may have the same pathology (i.e., multifocal BAC). When a GGO lesion is located deep in the hilum or multiple lesions are scattered in different lobes in patients with multifocal BAC, it can be difficult to resect them all. Yet, it has also not been determined whether these lesions should be resected or followed by serial computed tomography (CT) scans. Few reports have demonstrated the fate of pure GGO lesions in cases where some are not resected and then followed by CT scans. The objectives of this study were to (1) evaluate the clinical characteristics and long-term outcome of multiple pure GGO lesions detected in patients undergoing pulmonary resection for BAC and (2) report the fate and follow-up outcome of unresected, residual GGO lesions. PATIENTS AND METHODS Between January 2000 and December 2007, 2361 patients underwent pulmonary resection for non-small cell lung cancer at our institution. Pathologic examinations revealed that among these, 73 patients had BAC according to the recently revised World Health Organization classification of lung tumors. 14 Of these, 23 patients had multiple pure GGO lesions on preoperative CT scans and were included in the study population. Patients who had single GGO lesion were excluded. Patients who had GGO lesions with a solid component ( mixed GGO ) were excluded. Patients who had adenocarcinoma with BAC features were also excluded. Medical records were retrospectively reviewed to investigate the clinical characteristics, GGO features, histopathologic results, and follow-up outcomes. This study was reviewed and approved by the Institutional Review Board of Samsung Medical Center. 206 Journal of Thoracic Oncology Volume 5, Number 2, February 2010

2 Journal of Thoracic Oncology Volume 5, Number 2, February 2010 Multiple Pure Ground-Glass Opacity Lesions In patients with multiple pure GGO lesions, we tried to resect pure GGO lesions larger than 10 mm regardless of the location. For pure GGO lesions smaller than 10 mm, if the extent of resection was expected to be greater than lobectomy due to the central location or if there were multiple lesions scattered throughout multiple lobes, we decided not to resect such lesions and instead closely follow them using serial CT scans. No patients underwent percutaneous fine needle aspiration or transbronchial biopsy via bronchoscopy. All patients were regularly evaluated by CT scans every 3 months for the first 2 years after surgery, and then every 6 months thereafter regardless of whether or not all GGO lesions were resected. Descriptive statistics were used to summarize patient characteristics and outcomes. The normally distributed, continuous data were expressed as mean SD. Categorical data were expressed as counts and proportions. Significance was defined as a p value less than RESULTS Clinical Findings Patient characteristics and GGO features are summarized in Table 1. There were 11 men (48%) and 12 women (52%), with a mean age of years (range, years). Fifteen patients (65%) had no history of smoking. No patients had a history of malignancy except for one who had a colon cancer. A total of 89 GGO lesions were detected in 23 patients, and the median number of GGO lesions per patient was 3 (range, 2 11). The median size of GGO lesions was 5 mm (range, 3 40). The mean diameter of the resected GGO lesions was 9 mm, whereas the mean diameter of those that were followed with imaging studies was 5 mm. GGO lesions TABLE 1. Clinical Characteristics and GGO Features Characteristics No. of patients (n) 23 Age at operation (yr, mean SD) (38 78) Male:female 11:12 History of smoking (n) Nonsmoker 15 Current smoker 7 Exsmoker 1 History of previous malignancy (n) No 22 Yes 1 a Total no. of GGO lesions (n) 89 No. of GGO lesions per patient, n, median (range) 3 (2 11) Size of GGO lesions, mm, median (range) 5 (3 40) Location (n) Bilateral 13 Unilateral 10 a Had a history of colon cancer. GGO ground-glass opacity. were detected bilaterally in 13 patients (57%) and unilaterally in 10 (43%). Typical images of CT scans are shown in Figure 1. Operative Procedures Operative procedures are listed in Table 2. Preoperative percutaneous CT-guided marking using a hook wire was performed in 16 patients (70%). Procedures were done using video-assisted thoracic surgery in 16 patients (70%). Wedge resection was performed in 12 patients (52%), lobectomy in 7 (30%), lobectomy with wedge resection in 3 (13%) and bilobectomy in 1 (4%). Of the 11 patients who had a lobectomy or bilobectomy, 8 underwent conversion from wedge resection to lobectomy because the possibility of adenocarcinoma could not be ruled out based on the intraoperative frozen section alone. Two patients underwent lobectomy for a deeply-located lesion and one for multiple lesions in a lobe. In all patients who underwent lobectomy or bilobectomy, systematic mediastinal lymph node dissection was done. Five patients (22%) had all GGO lesions resected, whereas 18 patients (78%) had some GGO lesions resected and the remaining lesions followed by serial CT scans. Early Outcomes No early mortality or morbidity occurred during the postoperative period. The mean duration of hospital stay was days (range, 2 14 days). Thirty-nine GGO lesions were resected, and the pathologic diagnoses included nonmucinous BAC in 26 lesions, atypical adenomatous hyperplasia in 10, anthracofibrosis in 2, and mucinous BAC in 1. All the 11 patients who underwent a mediastinal lymph node dissection had N0 disease. Late Outcomes The median follow-up duration was 40.3 months (range, months). No late death occurred during the follow-up period, and no patients developed a local recurrence or distant metastasis. Of the five patients who had all GGO lesions resected, four (80%) had no recurrences, whereas one (20%) developed a new lesion 49 months after the initial operation. The patient, who had undergone a bilobectomy for multifocal BAC, received a wedge resection for the newly developed lesion, which turned out to be adenocarcinoma. In the 18 patients who had some GGO lesions resected and the remaining lesions followed by CT scans, the residual lesions either did not change in size (n 15, 83%) or disappeared (n 3, 17%) in all patients. No GGO lesions increased in size or developed a solid component during the follow-up period. Patient demographics and follow-up outcomes are presented in Table 3. DISCUSSION GGO is a radiographic finding defined as hazy, increased attenuation of the lung with preservation of bronchial and vascular margins. 5 GGO features arise from a replacing growth pattern along the alveolar wall. 5 Because the pathology of GGO may be a neoplasm such as BAC or early-stage adenocarcinoma, many authors have investigated the correlation of radiologic findings with pathologic diagnosis When GGO lesions are substantially large (e.g., 10 mm) or Copyright 2010 by the International Association for the Study of Lung Cancer 207

3 Kim et al. Journal of Thoracic Oncology Volume 5, Number 2, February 2010 TABLE 2. Operative Procedures Surgical procedures Wedge resection 12 Lobectomy 10 Simple lobectomy 7 Lobectomy plus ipsilateral wedge resection 2 Lobectomy plus contralateral wedge resection 1 Bilobectomy 1 Rationale for lobectomy Possibility of invasive ADC on frozen section biopsy 8 Deep in parenchyma 2 Multifocal lesions in a lobe 1 ADC adenocarcinoma. FIGURE 1. Typical computed tomography scan images of multiple ground-glass opacity (GGO) lesions in 50-year-old asymptomatic woman. A, 8-mm round GGO nodule (arrow) in the left upper lobe. B, 9-mm oval GGO nodule (arrow) deep in the right upper lobe. C, 7-mm round GGO nodule (arrow) with slightly lobulated margin in the right lower lobe. have a solid component, the possibility of adenocarcinoma cannot be ruled out and they need to be surgically resected to confirm the pathology. 6 Conversely, pure GGO lesions, which have no solid component, suggest nonmucinous BAC or its precursors rather than adenocarcinoma. According to the World Health Organization classification of lung adenocarcinoma, the prerequisite for the diagnosis of BAC is that the lesions demonstrate pure lepidic growth without invasion of stroma, blood vessels, or pleura. 13 Therefore, patients with noninvasive BAC usually have better outcomes than those with invasive adenocarcinoma. Noguchi et al. 14 found out that small peripheral lung adenocarcinomas with a pure BAC pattern and no invasion had a 100% 5-year survival, whereas patients with mixed BAC and invasive components had a survival of 75%. BAC commonly appears as multiple pure GGO lesions. Using a novel strategy for clonality determination to examine BAC genetics, Barsky et al. 15 found that these tumors were mostly multifocal, independent cancers. This finding implies that multiple pure GGO lesions may be multifocal BAC if one lesion is pathologically confirmed as BAC. As long as it is feasible to remove all lesions, the treatment strategy of our institution for multifocal BAC is complete surgical resection. Because of the possibility of invasive neoplasm, pathologic confirmation is needed, particularly for lesions greater than 10 mm or with a solid component. Nevertheless, when one of the lesions is located deep in the hilum or multiple lesions are scattered in different lobes, it can be difficult to resect them all. Patients with marginal cardiopulmonary reserve may be unable to tolerate multiple or bilateral pulmonary resections. For those patients in whom complete surgical resection was not feasible, we decided to not resect some of the lesions and followed them using serial CT scans. We found that the remaining GGO lesions did not change in size or even disappeared, and no lesions increased in size or developed a solid component during the follow-up period. This outcome suggests that the remaining lesions might be noninvasive tumors such as BAC and that they have a very indolent natural course. Few reports have demonstrated the fate of multiple pure GGO lesions in cases where some are not resected and then followed with serial CT scans. Kodama et al. 7 investigated the natural history of pure GGO, focusing on single pure 208 Copyright 2010 by the International Association for the Study of Lung Cancer

4 Journal of Thoracic Oncology Volume 5, Number 2, February 2010 Multiple Pure Ground-Glass Opacity Lesions TABLE 3. Patient Demographics and Follow-up Outcomes Patient No. Group a Operation (yr) Age at Sex No. of Lesions Location Follow-up Duration (mo) Fate of Residual GGO 1 II 54 female 2 RML, RLL 110 Disappeared No 2 I 66 male 2 RML, RLL 68 NA Yes 3 II 69 female 7 RUL, LUL, LLL 55 No change No 4 II 78 female 5 RUL, RML, RLL, LUL 48 No change No 5 II 55 male 3 RML, LUL 46 No change No 6 II 57 female 2 RML, LUL 45 No change No 7 I 43 male 2 RLL, LLL 44 NA No 8 II 50 female 10 RUL, RLL, LUL 42 No change No 9 II 59 female 4 RUL, LUL, LLL 42 Disappeared No 10 II 46 female 3 RUL, LUL, LLL 41 No change No 11 II 58 female 2 LUL, LLL 41 No change No 12 II 58 male 4 RLL, LUL, LLL 40 No change No 13 II 62 female 3 RUL, RLL, LUL 40 Disappeared No 14 II 56 male 4 RUL, RLL 37 No change No 15 II 62 female 3 RLL, LLL 35 No change No 16 II 37 male 2 RUL, LLL 35 No change No 17 II 49 female 3 LUL, LLL 34 No change No 18 II 49 male 4 RUL, LUL 34 No change No 19 II 68 male 3 RUL, RLL, LUL 31 No change No 20 I 54 female 4 RUL, RLL 27 NA No 21 I 67 male 4 RUL, RML 26 NA No 22 I 59 male 2 RUL 24 NA No 23 II 50 male 11 RUL, LUL, LLL 23 No change No New Lesion a Patients had all GGO lesions resection in group I, whereas patients had some of the GGO lesions resection in group II. GGO ground-glass opacity; RUL right upper lobe; RML right middle lobe; RLL right lower lobe; LUL left upper lobe; LLL left lower lobe; NA not applicable. GGO lesions, and suggested that some pure GGO lesions never progress to clinical disease. We found similar results in our study of multiple pure GGO lesions, in which we saw no recurrences or cancer-related deaths during the follow-up period, even though some lesions were not resected. Patients with pure GGO lesions seem to have favorable outcomes, even if they have multiple lesions. Our favorable outcomes might be due to the relatively short duration of follow-up. Aoki et al. 16 demonstrated that BAC-pattern tumors (Noguchi type A or B) had longer tumor doubling times of more than 1 year, with a mean of 880 days, compared with 252 days of non BAC-pattern tumors (Noguchi types D, E, and F). Accordingly, persistent pure GGO lesions should be followed for a minimum of more than 1 year to conclude whether they are invasive or not. In fact, there are several reports on the malignancy potential of persistent GGO lesions that show no change in their size during follow-up. 17,18 Moreover, because the mean diameter of GGO lesions that we decided to not resect was only 5 mm, even doubling in three-dimensional volume might not have been detected using two-dimensional CT scans during the relatively short duration of follow-up. Nevertheless, it cannot be denied that pure GGO lesions might be less invasive, indolent BAC regardless of whether patients have single or multiple lesions. Therefore, when it is not easy to resect all GGO lesions based on the location and multiplicity of lesions or the functional status of the patient, close follow-up using serial CT scans represents another option. Nevertheless, the question remains of which lesions could be initially followed without surgical resection. First of all, mixed GGO lesions with a solid component should be resected regardless of size, because solid components are associated with areas of collapsed alveoli or fibroblastic proliferation, which signifies more invasive lesions than pure GGO lesions without a solid component. Many authors have reported that the solid components in advanced stage lesions are significantly larger than those in lesions at earlier stages. 19,20 Second, GGO lesions larger than 10 mm should also be resected. Nakata et al. 6 noted that all lesions larger than 10 mm were carcinoma, without exception. In our series, we only decided not to perform surgical resection on lesions smaller than 10 mm. Last, centrally located GGO lesions can be followed to avoid multiple lobectomies or extensive bilateral pulmonary resections unless the lesions are larger than 10 mm or have a solid component. If the lesions show any change in size or nature on CT scans during follow-up, surgical resection should be considered for those lesions in selected patients. There are no established guidelines regarding the optimal extent of resection for multifocal BAC. Limited resection is inevitable for patients with multifocal BAC because of the number of lesions. Nakata et al. 21 reported successful results Copyright 2010 by the International Association for the Study of Lung Cancer 209

5 Kim et al. Journal of Thoracic Oncology Volume 5, Number 2, February 2010 using thoracoscopic wedge resection for pure GGO lesions selected on HRCT images. They indicated that the area of GGO on HRCT images could be a useful criterion for selecting surgical procedures, and that wedge resection could be valid for pure GGO lesions. Mun et al., 22 in their retrospective review of 27 patients with multifocal BAC, demonstrated that video-assisted thoracic surgery pulmonary resection was feasible and yielded satisfactory outcomes. They tried to resect all lesions in every case by wedge resection or lobectomy. In our study, although some patients received a lobectomy or even bilobectomy due to the location or number of the lesions, most patients underwent multiple wedge resections for multifocal lesions. Considering that BAC is defined as a noninvasive neoplasm, limited resection such as wedge resection could be sufficient for each pure GGO lesion. Our study has several limitations. First, as mentioned above, the follow-up duration was rather short. Further observation for a longer period might have revealed changes in the size or nature of the remaining GGO lesions. Second, our data were retrospectively collected in a small series. For results that are conclusive and persuasive, prospective data acquisition from a large cohort is needed. Third, in cases with multiple GGO lesions where only one lesion was pathologically confirmed, there is no guarantee that the pathologically confirmed lesion represented the remaining lesions. Although we excluded GGO lesions with a solid component so that all of the lesions had a similar morphology, we cannot definitely conclude that the lesions had the same histopathological diagnosis. 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